CN1217943C - New use and novel N-azabicyclo-amide derivatives - Google Patents

New use and novel N-azabicyclo-amide derivatives Download PDF

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CN1217943C
CN1217943C CN008184216A CN00818421A CN1217943C CN 1217943 C CN1217943 C CN 1217943C CN 008184216 A CN008184216 A CN 008184216A CN 00818421 A CN00818421 A CN 00818421A CN 1217943 C CN1217943 C CN 1217943C
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oct
azabicyclo
acrylamide
phenyl
compound
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CN1423651A (en
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M·巴勒斯特拉
G·穆伦
E·菲利普斯
R·施米辛
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AstraZeneca AB
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Abstract

This invention relates to new use of a compound of general formula (I) wherein: A represents (II), (III), (IV), (V), (VI); D represents oxygen, or sulfur; R<1> represents hydrogen or methyl; R<2> represents hydrogen, or C1-C4 alkyl; and R<3> represents (A), (B), (C), or an enantiomer thereof, and pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially in the treatment of prophylaxis of psychotic disorders and intellectual impairment disorders.

Description

New purposes and new N-azabicyclo-amide derivatives
Technical field
The present invention relates to rubane acrylamide or their pharmacy acceptable salt new medical use, prepare their method and comprise their medicinal compositions.The present invention also relates to some new rubane acrylamides or their pharmacy acceptable salt, prepare their method and comprise their medicinal compositions.Especially the present invention relates to the purposes that the rubane acrylamide is used to prepare the medicine of treatment or prevention psychosis or intellectual damage disease, and treat and/or prevent purposes in the medicine that wherein activates disease that alpha 7 nicotinic receptor is useful people or symptom in preparation.
Background of invention
At (1995) such as McDonald " nicotinic acetylcholine receptor: molecular biology, chemistry and pharmacology ", Annual Reports in Medicinal Chemistry, the 30th volume, the 5th chapter, the 41-50 page or leaf, Academic Press Inc., San Diego, CA and Williams etc. (1994) " neuronal nicotinic acetylcholine receptor ", Drug News; Perspectives; the 7th volume; in the 205-223 page or leaf; discussed in conjunction with the compound of the nicotinic acetylcholine receptor purposes in the treatment multiple disease relevant, having comprised with the reduction cholinergic function: for example presenile dementia, cognition or attention disorders, anxiety disorder, dysthymia disorders, stop smoking, neuroprotective, schizophrenia, analgesia, Tourette's syndrome and Parkinson's disease.
As the new pharmacological use that the present invention has found, has effect from the more known rubane acrylamide derivatives of EP 581165-A2 as cough medicine.The antitussive activity of these compounds is described to " to not effect of central nervous system ", and does not propose these compounds and be used for the treatment of purposes with the central nervous system diseases associated.
Disclosure of the Invention
According to the present invention, found that the compound of general formula I or its enantiomorph and pharmacy acceptable salt thereof are used to prepare the medicine of treatment or prevention psychosis or intellectual damage disease,
Figure C0081842100161
Wherein:
A represents:
Figure C0081842100162
D represents oxygen or sulphur;
R 1Expression hydrogen or methyl;
R 2Expression hydrogen or C 1-C 4Alkyl;
R 3Expression:
R 4, R 5And R 6Independent is hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl ,-CO 2R 7,-CN ,-CF 3Or Ar, condition is R 4And R 5In at least one the expression Ar; Ar represents to comprise 5-or the 6-unit's aromatics or the heteroaromatic rings of 0-3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, 8-, the 9-or 10-unit's fused aromatic or the heteroaromatic rings system that perhaps comprise 0-4 nitrogen-atoms, a 0-1 Sauerstoffatom and 0-1 sulphur atom, it can be selected from by one or more, and following substituting group is optional to be replaced, and comprising: hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, aryl, heteroaryl ,-CO 2R 7,-CN ,-NO 2,-NR 8R 9,-CF 3,-OR 10
R 8, R 9And R 10Independent is hydrogen, C 1-C 4Alkyl, aryl, heteroaryl ,-C (O) R 11,-C (O) NHR 12,-C (O) R 13,-SO 2R 14, or R 8And R 9Can be (CH together 2) jQ (CH 2) k, wherein Q is O, S, NR 15Or key;
J is 2-4;
K is 0-2;
R 7, R 10, R 11, R 12, R 13, R 14And R 15Independent is C 1-C 4Alkyl, aryl or heteroaryl.
Such symptom, the example of disease or obstacle is a presenile dementia, the study defective, cognitive defect, absent minded, the loss of memory, scatterbrained hyperactivity disorder, anxiety disorder, schizophrenia, manic or manic depressive illness, thunder dimension corpusculum dementia, Parkinson's disease, Huntington Chorea, Tourette's syndrome, the neurodegenerative disease of cholinergic synapse (synapse) forfeiture wherein, jet lag, stop smoking, comprise and be exposed to the nicotine habituation that the product that contains nicotine causes, pain, with be used for ulcerative colitis.
Except as otherwise noted, C 1-C 4Alkyl referred to herein as for example methyl, ethyl, n-propyl, normal-butyl, sec.-propyl, isobutyl-, the tertiary butyl, sec-butyl, no matter separately or the part of another group can be straight chain or ramose, and C 3-C 4Alkyl also can be cyclic, for example cyclopropyl, cyclobutyl.
Except as otherwise noted, aryl refers to and can be comprised: halogen, C by 1-3 phenyl ring that is selected from the optional replacement of following substituting group 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl ,-CO 2R 7,-CN ,-NO 2,-NR 8R 9,-CF 3,-OR 10
Except as otherwise noted, heteroaryl refers to 5-or 6-unit's aromatics or the heteroaromatic rings that comprises 0-3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, condition is that described ring comprises at least one nitrogen, oxygen or sulphur atom, it can be selected from by one or more, and following substituting group is optional to be replaced, and comprises; Halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl ,-CO 2R 7,-CN ,-NO 2,-NR 8R 9,-CF 3,-OR 10
Except as otherwise noted, halogen refers to fluorine, chlorine, bromine or iodine.
Pharmaceutically acceptable derivates comprises solvate and salt.For example, formula I compound can form acid salt with acid, for example conventional, pharmaceutically acceptable acid, for example salt of toxilic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, fumaric acid, Whitfield's ointment, Citric Acid, lactic acid, amygdalic acid, tartrate and methylsulfonic acid.
The preferred embodiments of the invention comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, and wherein A represents:
Figure C0081842100181
The preferred embodiments of the invention also comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, and wherein D represents oxygen.
The preferred embodiments of the invention also comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, wherein R 2Expression hydrogen.
The preferred embodiments of the invention also comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, wherein R 3Expression:
The preferred embodiments of the invention also comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, wherein R 3Expression
Work as R 4During expression Ar, R 5Expression hydrogen or C 1-C 4Alkyl; R 6The expression hydrogen or halogen;
The preferred embodiments of the invention also comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, and wherein A represents:
Figure C0081842100191
D represents oxygen;
R 2Expression hydrogen;
R 3Expression:
The preferred embodiments of the invention also comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, and wherein A represents:
D represents oxygen;
R 2Expression hydrogen;
R 3Expression:
Figure C0081842100194
R 4Expression Ar;
R 5Expression hydrogen or C 1-C 4Alkyl;
R 6The expression hydrogen or halogen.
The preferred embodiments of the invention also comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, wherein Ar represents to comprise 5-or the 6-unit's aromatics or the heteroaromatic rings of 0-3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, 8-, the 9-or 10-unit's fused aromatic or the heteroaromatic rings system that perhaps comprise 0-4 nitrogen-atoms, a 0-1 Sauerstoffatom and 0-1 sulphur atom, it can be selected from by one or more, and following substituting group is optional to be replaced, and comprising: hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, aryl, heteroaryl ,-CO 2R 7,-CN ,-NO 2,-NR 8R 9,-CF 3,-OR 10
The preferred embodiments of the invention also comprise formula I compound or its enantiomorph and pharmacy acceptable salt thereof, and wherein A represents:
Figure C0081842100201
D represents oxygen;
R 1And R 2Be hydrogen;
R 3Expression:
Or R 3Expression:
Wherein:
R 4Expression Ar;
R 5Expression hydrogen or C 1-C 4Alkyl;
R 6The expression hydrogen or halogen;
Ar represents to comprise 5-or the 6-unit's aromatics or the heteroaromatic rings of 0-3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, comprise: phenyl, 2-, 3-or 4-pyridyl, 2-or 3-furyl and 2-or 3-thienyl, in them any one can be selected from the optional replacement of following substituting group by one or more, comprising: hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl ,-CO 2R 7,-CN ,-NO 2,-NR 8R 9,-CF 3,-OR 10
Preferred formula I compound comprises following compound:
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) (3-phenyl propine acid amides);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [Z-3-(2-p-methoxy-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl)-N-methyl-(E-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-2-benzyl ring propane-1-methane amide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-2-fluoro-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-formamido-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-nitrophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-aminophenyl) acrylamide;
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-formamido-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-methyl-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N-methylamino phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N, N-dimethylaminophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-methyl-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2,3-phenylbenzene propylene acid amides);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-p-methoxy-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-methyl-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminomethyl phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-p-methoxy-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-fluorophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-fluorophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-chloro-phenyl-) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-chloro-phenyl-) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-chloro-phenyl-) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3, the 4-dichlorophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-bromophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-bromophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-iodophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-iodophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-trifluoromethyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-trifluoromethyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-nitro-2-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide];
N-(interior-the 8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide);
N-(outer-8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide); Or its enantiomorph and pharmacy acceptable salt thereof.
Particularly preferred formula I compound comprises following compound:
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide);
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide);
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (3-phenyl propine acid amides);
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (3-phenyl propine acid amides);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [Z-3-(2-p-methoxy-phenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl)-N-methyl-(E-3-Phenyl Acrylamide);
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-2-benzyl ring propane-1-methane amide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-2-benzyl ring propane-1-methane amide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-2-fluoro-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-formamido-phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-nitrophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-(4-aminophenyl) acrylamide;
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-formamido-phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-methyl-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N-methylamino phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N, N-dimethylaminophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-methyl-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2,3-phenylbenzene propylene acid amides);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-p-methoxy-phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-methyl-3-Phenyl Acrylamide);
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-methyl-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminomethyl phenyl) acrylamide];
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminomethyl phenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-p-methoxy-phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-p-methoxy-phenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-p-methoxy-phenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-fluorophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-fluorophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-fluorophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-chloro-phenyl-) acrylamide];
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-chloro-phenyl-) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-chloro-phenyl-) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-chloro-phenyl-) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3, the 4-dichlorophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-bromophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-bromophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-iodophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-iodophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-trifluoromethyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-trifluoromethyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-nitro-2-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide];
N-(interior-the 8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide);
N-(outer-8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide);
Or its enantiomorph and pharmacy acceptable salt thereof.
In another aspect of the present invention, new compound or its enantiomorph and the pharmacy acceptable salt thereof of formula I are provided, they are efficient ligands of nicotinic acetylcholine receptor, other condition is that Ar does not represent 2-, 3-, 4-pyridyl, unsubstituted phenyl or is selected from the phenyl that following substituting group replaces by one or more, comprising: C 1-C 4Alkyl, C 1-C 4Alkoxyl group, halogen, phenoxy group, hydroxyl, OCOR 11, NH 2, NHCOR 11And nitro, when A represents
Or During VI;
R 3Expression:
Figure C0081842100263
D represents oxygen;
R represents methyl;
R 2And R 5All represent hydrogen;
R 6Expression hydrogen, C 1-C 4In alkyl, phenyl or the cyano group any one.
In this embodiment preferred on the one hand of the present invention, formula I compound or its enantiomorph and pharmacy acceptable salt thereof as above definition are provided, wherein A represents:
Figure C0081842100264
In this another embodiment preferred on the one hand of the present invention, formula I compound or its enantiomorph and pharmacy acceptable salt thereof as above definition are provided, wherein A represents:
And R 6In expression 2-furyl, 3-furyl, 2-thienyl, the 3-thienyl any one.
In these compounds, following compound is preferred:
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-trifluoromethyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide];
N-(1-azepine-3-cyano-bicyclo [2.2.2] oct-3-yl) [E-3-Phenyl Acrylamide];
N-(1-azepine-3-methyl bicycle [2.2.2] oct-3-yl) [E-3-Phenyl Acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-nitro-2-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide]; Or its enantiomorph and/or pharmacy acceptable salt.
In these compounds, following compound is for preferred especially:
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-trifluoromethyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide];
N-(1-azepine-3-cyano-bicyclo [2.2.2] oct-3-yl) [E-3-Phenyl Acrylamide];
N-(1-azepine-3-methyl bicycle [2.2.2] oct-3-yl) [E-3-Phenyl Acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-nitro-2-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide].
Pharmaceutically acceptable derivates comprises solvate and salt.For example, formula I compound can form acid salt with acid, for example conventional, pharmaceutically acceptable acid, for example salt of toxilic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, fumaric acid, Whitfield's ointment, Citric Acid, lactic acid, amygdalic acid, tartrate and methylsulfonic acid.
The compounds of this invention has following favourable condition, and they can be that toxicity is lower, more efficacious, action time is longer, has activity widely, and is more effective, produces side effect still less, is easier to absorb or have other useful pharmacological property.
The preparation method
At reaction process and hereinafter, except as otherwise noted, A, R 1, R 2And R 3Define to formula I as above.According to the method for general introduction in flow process 1, but preparation I compound.
Figure C0081842100291
Flow process 1.
Use suitable process for acylating, by with the reaction of formula VIII compound, wherein Y represents the leavings group that suits, can prepare the formula I compound that D wherein represents oxygen from formula VII compound.Suitable leavings group Y comprises: OH, halogen, O alkyl, O aryl, OCO alkyl, OCO aryl, azido-.Suitable process for acylating is included in the suitable solvent, under 0-120 ℃, with formula VIII compound treatment formula I compound.The existence of alkali, or the existence of coupler when Y=OH also can be necessary to the generation of reaction.Comprise reacting suitable alkali: 4-(N, N-dimethylamino) pyridine, pyridine, triethylamine, N, N-diisopropylethylamine.Preferred alkali is N, the N-diisopropylethylamine.Coupler suitable when Y=OH comprises: carbodiimide, for example 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride; Phosphonium reagent, for example phosphofluoric acid benzotriazole-1-base oxygen base three (dimethylamino) Phosphonium or phosphofluoric acid benzotriazole-1-base oxygen base tripyrrole Wan Ji Phosphonium; And urea (uronium) reagent, Tetrafluoroboric acid O-benzotriazole-1-base-N for example, N, N ', N '-tetramethyl-urea.Preferred coupler is Tetrafluoroboric acid O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea.This reaction The suitable solvent is comprised N, dinethylformamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) or chloroform.Preferred solvent is N, dinethylformamide.Reaction is preferably carried out under 0-50 ℃ temperature, and most preferably carry out under 20-30 ℃ temperature.
Perhaps, in the presence of suitable acid, in The suitable solvent, by nitrile processing with formula X, can from formula IX compound wherein D represent oxygen and R 2The formula I compound of expression hydrogen.Suitable acid comprises sulfuric acid, and The suitable solvent comprises acetate.Be reflected under 0-50 ℃ the temperature and carry out, and preferably under 0-25 ℃ temperature, carry out.
In The suitable solvent, by with suitable sulfide reaction, represent that from D wherein the formula I compound of oxygen can prepare the formula I compound that D wherein represents sulphur.Preferred sulfide is phosphoric sulfide, especially 4-p-methoxy-phenyl thionophosphine sulphides dimer (" LawessonShi reagent ") and thiophosphoric anhydride.The suitable solvent that is used for this reaction comprises aromatic solvent, for example toluene or dimethylbenzene.Be reflected under 0-200 ℃ the temperature and carry out, and preferably under 50-180 ℃ temperature, carry out.
By suitable alkylation, from R wherein 2The formula VII compound of expression hydrogen can prepare wherein R 2The formula VII compound of expression alkyl.General alkylation be included in The suitable solvent for example among the DMF with suitable alkylogen or sulphonate and alkali for example sodium hydride handle, or in inert solvent, use reductive alkylation with the suitable aldehydes or ketones of the reductive agent that suits.Preferable methods is a reductive alkylation.Suitable reductive agent comprises sodium borohydride and sodium cyanoborohydride.Preferred reductive agent is a sodium borohydride.Suitable inert solvent comprises water, methyl alcohol or ethanol.Preferred solvent is a methyl alcohol.Reaction is preferably carried out under 20-65 ℃ temperature usually at 0-100 ℃.
Formula VII compound is available on the marketly maybe can prepare by method known to those skilled in the art.For example, the Ritter reaction by adopting suitable nitrile with after hydrolysis generates acid amides, can prepare some formula VII compounds from formula IX compound.
Formula VIII and X compound are available on the marketly maybe can prepare by method known to those skilled in the art.Referring to for example, in " the Comprehensive Organic Transformations " of R.C.Larock (VCH Publishers, 1989), method of quoting in the 819-995 page or leaf and the general reference of in the 823rd page of identical article, quoting.
One of ordinary skill in the art would recognize that by using the aromatics substitution reaction, or functional group changes modifying already present substituting group, or their combination, aromatic substituents that some are chosen wantonly can in The compounds of this invention, be introduced.Such reaction can be carried out or carry out rapidly after above-mentioned method in advance, and is included as the part of the inventive method aspect.The reagent of these class methods and reaction conditions are known in the art.But the specific examples of using method for example includes, but is not limited to make aromatic ring parent electricity functionalized by nitrated, halo or acidylate; For example change nitro into amino as catalytic hydrogenation by reduction; The acidylate of amino or hydroxyl, alkylation or sulfonylation; By changing the intermediate diazonium salt into, amino by another functional group's displacement with after nucleophilic or free radical replace diazonium salt; Or by nucleophilic or catalysis substitution reaction by another functional group's displacement halogen.
In case of necessity, use as the standard textbook " Protecting Groupsin Organic Synthesis " at Greene and Wuts, blocking group of describing in the 3rd edition (1999) can be protected hydroxyl, amino or other reactive group.
Except as otherwise noted, reaction described above can preferably be carried out under environmental stress (about 1 normal atmosphere) under about about 3 normal atmosphere of 1-usually.Except as otherwise noted, described above being reflected in the inert atmosphere preferably carried out in nitrogen atmosphere.
By standard technique, can from their reaction mixture, separate The compounds of this invention and intermediate.
The acid salt of the formula I compound that can be mentioned comprises the salt of mineral acid, for example hydrochloride and hydrobromate and the salt that forms with organic acid, for example formate, acetate, maleate, benzoate, tartrate and fumarate.
The free alkali by making them or derivative and monovalent or more a plurality of normal suitable acid-respons of salt, enantiomorph or protection can form the acid salt of formula I compound.Reaction therein salt be insoluble solvent or vehicle or therein salt be to carry out in the solvent of solubility, the mixture of water, diox, ethanol, tetrahydrofuran (THF) or ether or solvent for example, but their vacuum are removed or are removed through lyophilize.Reaction can be replacement process or can carry out on ion exchange resin.
Formula I compound exists with the form of tautomer or enantiomorph, and their form of ownership includes within the scope of the present invention.By using routine techniques, for example fractional crystallization or chirality HPLC, the racemic mixture of separating compound, separable different optical isomer.Perhaps, under the reaction conditions that does not cause racemization,, can prepare each enantiomorph by making suitable optical activity raw material reaction.
Medicinal compositions
The present invention relate on the other hand be used for the treatment of or prevent as following illustrational in the preferred people of Mammals by the medicinal compositions of caused symptom of nicotinic acetylcholine receptor neurotransmission dysfunction or disease, this medicinal compositions comprises a certain amount of formula I compound, its enantiomorph or its pharmacy acceptable salt that is effective to treat or prevent such disease or symptom and inertia, pharmaceutically acceptable diluent or carrier.
Being can be psychosis or intellectual damage disease or wherein activated alpha 7 nicotinic receptor by caused symptom of nicotinic acetylcholine receptor neurotransmission dysfunction or disease in the preferred people of Mammals is useful disease or symptom.Such symptom, the example of disease or obstacle comprises presenile dementia, the study defective, cognitive defect, absent minded, the loss of memory, scatterbrained hyperactivity disorder, anxiety disorder, schizophrenia, manic or manic depressive illness, thunder dimension corpusculum dementia, Parkinson's disease, Huntington Chorea, Tourette's syndrome, the neurodegenerative disease of cholinergic synapse forfeiture wherein, jet lag, stop smoking, comprise and be exposed to the nicotine habituation that the product that contains nicotine causes, pain or ulcerative colitis.
Certainly, for above-mentioned purposes, the dosage that is given will change with employed compound, administering mode and the treatment that needs.Yet generally the dosage with the about 20mg of the about 0.1mg-of every kg the weight of animals gives when The compounds of this invention every day, and can obtain the result that be satisfied with when giving with divided dose 1-4 time or with the slowly-releasing form preferred every day.For the people, total per daily dose is at 5mg-1, and 400mg more preferably changes in the scope of 10mg-100mg, and the formulation that is suitable for oral administration comprises the 2mg-1 with solid or liquid, medicinal carrier or mixing diluents, 400mg compound.
Formula I compound or its enantiomorph and pharmacy acceptable salt thereof can itself or use with the form of the suitable pharmaceutical preparation that is used for enteron aisle or parenterai administration.According to a further aspect in the invention, provide to comprise and inertia, pharmaceutically acceptable diluent or carrier blended, preferably be less than 80% and more preferably less than the medicinal compositions of the The compounds of this invention of 50% weight.
The example of thinner and carrier is:
-for tablet and dragee: lactose, starch, talcum powder, stearic acid; For capsule: tartrate or lactose;
-for injection solution: water, alcohols, glycerine, vegetables oil; For suppository: natural or winterized stearin or wax.
The method of the such medicinal compositions of preparation also is provided, and this method comprises mixes each component.
Purposes
One aspect of the invention is disease that The compounds of this invention, its enantiomorph or its pharmacy acceptable salt mention or the purposes in a kind of medicine in the symptom below preparation is used for the treatment of or prevents, with be used for the treatment of or prevent a kind of method in above-mentioned disease or the symptom, this method comprises The compounds of this invention or its enantiomorph or its pharmacy acceptable salt that gives the patient treatment significant quantity.
The compound that the present invention uses is nicotinic acetyl choline receptor agonists.Although without being limited by theory, be sure of α 7The agonist of nAChR (nicotinic acetylcholine receptor) hypotype should be effectively in treatment or prevention psychosis and intellectual damage disease and have above those also is α 4The advantage of the compound of nAChR subtype agonist.Therefore, to α 7The nAChR hypotype has optionally, and compound is preferred.The compounds of this invention is applicable to as the medicine of especially treating or prevent psychosis and intellectual damage disease.Psychotic example comprises schizophrenia, manic or manic depressive illness and anxiety disorder.The example of intellectual damage disease comprises presenile dementia, thunder dimension corpusculum dementia, study defective, cognitive defect, absent minded, the loss of memory and scatterbrained hyperactivity disorder.The compounds of this invention is as also being effectively at the anodyne of treatment pain (comprising chronic pain) with treating or preventing in the following disease, and comprising: Parkinson's disease, Huntington Chorea, Tourette's syndrome reach the wherein neurodegenerative disease of cholinergic synapse forfeiture.Described in addition compound is applicable to treatment or prevention jet lag, is used to induce stop smoking and be used for the treatment of or prevent nicotine habituation (comprise and be exposed to the habituation that the product that contains nicotine causes).
Be sure of that also The compounds of this invention is effective in treatment and prevention of ulcerative colitis.
Pharmacology
In the test of following elaboration, can measure the pharmacologically active of The compounds of this invention.
A-is to α in test 7The test of nAChR hypotype affinity
125I-α-bungatotoxin (BTX) is to the combination of rat hippocampus film: at the cold homogenizing damping fluid (HB: component concentrations (mM): three (hydroxymethyl) aminomethane 50 of 20 volumes; MgCl 21; NaCl120; KCl5:pH7.4) in, with the rat hippocampus homogenizing.Under 1000g, with centrifugal 5 minutes of homogenate, the taking-up supernatant liquor was laid equal stress on and is extracted precipitation.Under 12000g,, and be resuspended among the HB centrifugal 20 minutes of the supernatant liquor that merges, flushing.Under 21 ℃, film (30-80 μ g) and 5nM[ 125I] α-BTX, 1mg/mL BSA (bovine serum albumin(BSA)), be subjected to reagent thing and 2mM CaCl 2Or 0.5mM EGTA[ethylene glycol-two (beta-amino ether)] hatched together 2 hours, use the Brandel cell harvestor then, filter and wash 4 times through Whatman glass fiber filter (thickness C).(3 hours these filter membranes of BSA/0.01%PEI (polymine) pre-treatment are vital to low filter membrane blank (per minute 0.07% grand total) to be used in 1% in the water.Describe non-specific binding through 100 μ M (-) nicotine, and specificity is in conjunction with being generally 75%.
B-is to α in test 4NAChR hypotype compatibility test
[ 3H]-combination of (-) nicotine: use Martino-Barrows and Kellar improve one's methods (MolPharm (1987) 31:169-174), as [ 125I] α-BTX in conjunction with in the test like that, with rat brain (cortex and hippocampus) homogenizing, 12, under the 000xg centrifugal 20 minutes, wash 2 times, be resuspended to then among the HB that contains 100 μ M fluoro di(2-ethylhexyl)phosphate isopropyl esters.At 4 ℃ after following 20 minutes, under 4 ℃, with film (approximately 0.5mg) and 3nM[ 3H]-(-) nicotine, be subjected to reagent thing, 1 μ M coromegine and 2mM CaCl 2Or 0.5mM EGTA hatched 1 hour together, used the Brandel cell harvestor then, filtered through Whatman glass fiber filter (thickness C) (with 0.5%PEI pre-treatment 1 hour).Describe non-specific binding through 100 μ M carbechals, and specificity is in conjunction with being generally 84%.
The binding data analysis of test A and test B
(DeLean A, Munson P J and Rodbard D (1977) Am.J.Physiol. 235:E97-E102), calculate IC to use non-linear curve fitting program ALLFIT 50Value and pseudo-Hill coefficient (n H).Use non-linear regression ENZFITTER (Leatherbarrow, R.J. (1987)), saturation curve be fit to a point model, obtain respectively to [ 125I]-K of α-BTX DThe value 1.67nM and to [ 3H]-K of (-) nicotine part DValue 1.70nM.Use total Cheng-Prusoff equation to estimate K iValue:
K i=[IC 50]/((2+ ([part]/[K D]) n) 1/n-1) wherein works as n H＜1.5 o'clock, use the value of n=1, and work as n H〉=1.5 o'clock, the value of use n=2.Sample revision test three times and being generally ± 5%.Use 6 or more a plurality of drug level, measure K iValue.The compounds of this invention is binding affinity (K in test A or test B i) less than the compound of 10 μ M, show that they are had effective therapeutic activity by expectation.
Use The compounds of this invention to have advantageous conditions, they can be that toxicity is lower, more efficacious, action time is longer, have activity widely, and are more effective, produce side effect still less, are easier to absorb or have other useful pharmacological property.
The logical method of experiment
The reagent of buying can use without being further purified.Mass spectrum uses Hewlett Packard5988A or MicroMass Quattro-1 mass spectrograph to write down and with m/z the parent molecule ion is reported.Room temperature refers to 20-25 ℃.
Embodiment
Following examples are for embodying preferred, the non-limiting example of preferred aspect of the present invention.
Embodiment 1
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide)
Under nitrogen atmosphere, at anhydrous N, in the dinethylformamide (570mL), (7.5g, 0.038mol) (5.6g 0.038mol) mixes with the E-3-phenylacrylic acid with (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride.The mixture that stir to generate, add simultaneously the I-hydroxybenzotriazole monohydrate (5.8g 0.0378mol), adds Tetrafluoroboric acid O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea (12.1g, 0.038mol) and N, N-diisopropylethylamine (26.4mL).At ambient temperature, solution stirring 6 hours, be placed in the refrigerator then and spend the night.This solution of vacuum concentration is handled resistates in chloroform (360mL), with aqueous sodium hydroxide washes wash (1M, 360mL).Use chloroform. extract alkaline layer more than twice.Merge organic layer, dry (MgSO 4), vacuum concentration.Through quick silicagel column purifying compounds, with 5-20% methyl alcohol/chloroform/ammonium hydroxide gradient elution.Prepare hydrochloride from Virahol and ethyl acetate, obtain 9.5g and show pale powder slightly; MS (ES +) 257 (MH +).
Embodiment 2
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide)
By with embodiment 1 in the similar approach described, prepare free alkali from (S)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-phenylacrylic acid; MS (ES +) 257 (MH +).
Embodiment 3
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide)
By with embodiment 1 in the similar approach described, prepare free alkali from (RS)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-phenylacrylic acid; MS (ES +) 257 (MH +).
Embodiment 4
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (3-phenyl propine acid amides)
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and 3-phenyl propynoic acid; MS (ES +) 255 (MH +).
Embodiment 5
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (3-phenyl propine acid amides)
By with embodiment 1 in the similar approach described, prepare free alkali from (S)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and 3-phenyl propynoic acid; MS (ES +) 255 (MH +).
Embodiment 6
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-nitrophenyl) vinylformic acid; MS (ES +) 302 (MH +).
Embodiment 7
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (S)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride with as solid E-3-(2-nitrophenyl) vinylformic acid;
MS(ES +)302(MH +)。
Embodiment 8
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (RS)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride with as solid E-3-(2-nitrophenyl) vinylformic acid; MS (ES +) 302 (MH +).
Embodiment 9
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminophenyl) acrylamide]
With prepared (RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide] (0.42g 0.014mol) is suspended in the acetone (4.2mL), and be added in ammonium chloride in the water (2.1mL) (0.15g, 0.028mol).Use oil bath that limpid solution is refluxed, (0.42g removes heating in the time of 0.063mol) to add zinc powder then.Under refluxing,, at this moment, confirm to finish conversion through tlc reaction solution heating 1 hour.With chloroform and saturated sodium bicarbonate diluted suspension, inclining from solid zinc liquid.Separate each layer, use the chloroform extraction water layer more than twice.Dry (MgSO 4) chloroform layer that merges, evaporation.In Virahol, prepare maleate.The decant solvent shifts the solid of orange humidity and except that desolvating, obtains the orange vitreum of spumescence with methyl alcohol; MS (ES +) 272 (MH +).
Embodiment 10
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminophenyl) acrylamide]
By with embodiment 9 in the similar approach described, prepare from (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide]; MS (ES +) 272 (MH +).
Embodiment 11
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [Z-3-(2-p-methoxy-phenyl) acrylamide]
By with embodiment 1 in the similar approach described, from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and the preparation of Z-3-(2-p-methoxy-phenyl) vinylformic acid; MS (ES +) 287 (MH +).
Embodiment 12
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl)-N-methyl-(E-3-Phenyl Acrylamide)
Under nitrogen atmosphere, (0.15g 0.059mol) is suspended in the anhydrous tetrahydro furan with (RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide).Use the ice bath reaction mixture, during be added dropwise to commercially available 1.0M borine/tetrahydrofuran (THF) mixture (0.59mL) through syringe.Suspension rapidly dissolving and under 0 ℃ with solution stirring 1 hour.Follow cooling down, through adding the careful quencher reaction of entry (2mL).Then, with salt solution and methylene dichloride diluting reaction thing.Separate each layer, use the dichloromethane extraction water layer more than twice.Dry (MgSO 4) organic layer that merges, vacuum-evaporation.Under nitrogen atmosphere, (28mg 0.00071mol) is suspended in anhydrous N, in the dinethylformamide (2mL) with sodium hydride.The crude product borane complexes is dissolved in N, in the dinethylformamide (1mL) and be added dropwise to.At room temperature, reaction solution was stirred 30 minutes, then through syringe add methyl iodide (55 μ L, 0.000885mol).Stir after 2.5 hours, with ice bath cooling reaction solution and water (1mL) quencher.With saturated sodium bicarbonate and ethyl acetate diluted suspension, separate each layer.Extract water layer more than twice, merge organic layer, dry (MgSO 4), vacuum concentration.Be dissolved in the crude product mixture in the acetone (1.6mL) and add entry (0.27mL).Cool off reaction solution with ice bath, be added dropwise to hydrobromic acid aqueous solution (0.27mL).Under 0 ℃, stirring reaction liquid.After 5 hours, add other Hydrogen bromide (0.27mL), further change but detect nothing through thin layer chromatography.Vacuum is removed acetone and is added 1 part of methyl alcohol and 3 parts of ethanol are further removed acetone.Successively grind crude product with ethanol and ether.Generate two-phase, separate lower floor also again with the ether washing, with its decant.Vacuum is removed remaining solvent.It is yellow semi-solid to use methyl alcohol to shift, and vacuum is removed methyl alcohol, if add two parts further to remove methyl alcohol with ether.Obtain 0.15g; MS (ES +) 271 (MH +).
Embodiment 13 and 14
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-benzyl ring propane-1-methane amide)
By with embodiment 1 in the similar approach described, prepare free alkali from (S)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and trans-2-benzyl ring propane-1-formic acid.Can separate diastereomer through silica gel chromatography, use 10-30% methyl alcohol/chloroform/ammonium hydroxide gradient elution; Both MS (ES +) 271 (MH +).
Embodiment 15 and 16
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-benzyl ring propane-1-methane amide)
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and trans-2-benzyl ring propane-1-formic acid.Can separate diastereomer through silica gel chromatography, use 10-30% methyl alcohol/chloroform/ammonium hydroxide gradient elution; Both MS (ES +) 271 (MH +).
Embodiment 17
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-2-fluoro-3-Phenyl Acrylamide)
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and Z-2-fluoro-3-phenylacrylic acid; MS (ES +) 275 (MH +).
Embodiment 18
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-formamido-phenyl) acrylamide]
Under inert atmosphere, with formic acid (98%, 2.9mL) and diacetyl oxide (1.0mL) mix, during cool off with cooling bath.(0.16g 0.00059mol), at room temperature stirs reaction solution 3 days to add (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-(2-aminophenyl) acrylamide).Solution is poured in the saturated sodium carbonate, adds more solid carbonate and be alkalescence up to solution.With chloroform water layer is extracted 4 times.Merge organic layer, dry (MgSO 4), vacuum concentration.Use the chloroform transfer product, remove and desolvate, add two parts of ether and further remove chloroform.At room temperature, the high vacuum dry white solid obtains 64mg; MS (ES +) 300 (MH +).
Embodiment 19
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-nitrophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(4-nitrophenyl) vinylformic acid; MS (ES +) 302 (MH +).
Embodiment 20
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-aminophenyl) acrylamide]
By with embodiment 9 in the similar approach described, prepare from (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-(4-nitrophenyl) acrylamide); MS (ES +) 272 (MH +).
Embodiment 21
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-formamido-phenyl) acrylamide]
By with embodiment 18 in the similar approach described, from (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-(4-aminophenyl) acrylamide) preparation free alkali; MS (ES +) 300 (MH +).
Embodiment 22
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-methyl-3-Phenyl Acrylamide)
(A) Z-3-methyl-3-phenyl propynoic acid
With cupric iodide (I) (1.1g 0.006mol) is suspended in the anhydrous diethyl ether (20mL), and the suspension that generates is remained on below-10 ℃, and lucifuge stirs, during slowly be added dropwise to commercially available 1.0M lithium methide solution (6mL).Under-10 ℃, white suspension was stirred 30 minutes, during the solid dissolving.Under-60 ℃, divide three parts add 3-phenyl propynoic acids (0.44g, 0.003mol).Then, under-10 ℃, reaction mixture was stirred 90 minutes, be poured in the diluted hydrochloric acid aqueous solution afterwards.Add chloroform, through the emulsion of diatomite filtration generation.Separate each phase then.With the chloroform extraction water layer more than 3 times.Merge organic layer, dry (MgSO 4), concentrate.High vacuum dry crude product solid can use without being further purified.
(B) (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-methyl-3-Phenyl Acrylamide)
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and Z-3-methyl-3-phenylacrylic acid; MS (ES +) 271 (MH +).
Embodiment 23
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N-methylamino phenyl) acrylamide]
Under nitrogen atmosphere, divide two parts with sodium Metal 99.5 (0.1g 0.0043mol) joins in the dry methyl alcohol (2mL) that is stirring under 0 ℃.After 20 minutes, (0.27g 0.001mol), adds paraformaldehyde (0.18g subsequently to be added in (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-aminophenyl) acrylamide] in the methyl alcohol, 0.006mol), at room temperature the solution stirring that generates is spent the night.Under 50 ℃, with reaction solution heating 4 hours, (0.10g 0.0028mol), heated solution 2 hours under refluxing to add sodium borohydride then.Make the reaction mixture cooling, and the adding potassium hydroxide aqueous solution (1M, 0.8mL).After at room temperature the mixture that generates being stirred 1 hour, this solution of vacuum concentration distributes resistates between water and chloroform.With the chloroform extraction water layer more than three times.Merge organic layer, dry (MgSO 4), vacuum concentration.At first, use 10-40% to contain ammonia methyl alcohol/chloroform gradient elution, then through WatersBondapak  C through silica gel solid phase extractions purifying mass 18Reversed-phase HPLC purifying mass on the post uses 10-60% acetonitrile and 0.1% trifluoroacetic acid aqueous solution gradient elution.Reclaim free alkali through neutralization and extraction, obtain the 45mg yellow powder; MS (ES +) 286 (MH +).
Embodiment 24
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N, N-dimethylaminophenyl) acrylamide]
In anhydrous methanol, with sodium cyanoborohydride (0.19g, 0.003mol) and Zinc Chloride Anhydrous (0.21g 0.0015mol) mixes.Mixture was stirred 5 minutes, add (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-aminophenyl) acrylamide] of being dissolved in the methyl alcohol (3mL) (0.27g, 0.001mol), add subsequently paraformaldehyde (0.18g, 0.006mol).At room temperature, the reaction mixture stirring is spent the night.Vacuum concentration methyl alcohol, dissolving resistates in 1M sodium hydroxide (20mL).With chloroform extraction water layer three times, merge these layers, dry (MgSO 4), vacuum-evaporation.At first, use 10-40% to contain ammonia methyl alcohol/chloroform gradient elution, then through Waters Bondapak  C through silica gel solid phase extractions purifying mass 18Reversed-phase HPLC purifying mass on the post uses 10-60% acetonitrile and 0.1% trifluoroacetic acid aqueous solution gradient elution.Reclaim free alkali through neutralization and extraction, obtain the 12mg yellow powder; MS (ES +) 300 (MH +).
Embodiment 25
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-Phenyl Acrylamide)
(A) Z-3-phenylacrylic acid
(0.16g 0.00063mol) is dissolved in the ethanol (6.3mL) and under nitrogen atmosphere and places with nickelous acetate (II) tetrahydrate.Green solution is stirred fast, during be added in sodium borohydride in the ethanol (0.63mL) (0.024g, 0.00063mol).Use then quadrol (0.42mL, 0.0063mol) handle this dark red purple solution add subsequently 3-phenyl propynoic acid (0.73g, 0.005mol).Under hydrogen, reaction solution was stirred 5 hours.Substitute hydrogen with nitrogen, through diatomite filtration suspension to remove catalyzer.Vacuum concentrated filtrate.In chloroform and water, dissolve resistates, add concentrated hydrochloric acid with the acidifying water layer.Separate each layer, use the chloroform extraction acidic layer more than three times.Merge organic layer, concentrate.Through Waters Bondapak  C 18Reversed-phase HPLC purifying mass on the post uses 10-40% acetonitrile and 0.25% trifluoroacetic acid aqueous solution gradient elution, obtains white solid (0.51g).
(B) (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-Phenyl Acrylamide)
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and Z-3-phenylacrylic acid; MS (ES +) 257 (MH +).
Embodiment 26
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-methyl-3-Phenyl Acrylamide)
(A) E-3-methyl-3-phenylacrylic acid
In anhydrous tetrahydro furan, prepare cupric bromide (I) (1.72g, 0.12mol) and lithiumbromide (1.0g, mixture 0.012mol) also is cooled to-50 ℃.(3.0M is in ether to be added dropwise to commercially available methylmagnesium-bromide; 4mL).Under-50 ℃, suspension was stirred 15 minutes, divide then add for three times 3-phenyl propynoic acid (0.44g, 0.003mol).Under-50 ℃, mixture was stirred 15 minutes, directly be warmed to 30 ℃ with warm water bath then.Stir after 1 hour, reaction mixture is poured in the saturated ammonium chloride.Make the solution acidifying through slowly adding concentrated hydrochloric acid, use chloroform extraction then four times.Merge organic layer, dry (MgSO 4), vacuum concentration.Through Waters Bondapak  C 18Reversed-phase HPLC purifying mass on the post uses 20-60% acetonitrile and 0.25% trifluoroacetic acid aqueous solution as gradient eluent, obtains colorless solid (0.14g).
(B) (R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-methyl-3-Phenyl Acrylamide)
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-methyl-3-phenylacrylic acid, provide filbert solid; MS (ES +) 271 (MH +).
Embodiment 27
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2,3-phenylbenzene propylene acid amides)
By with embodiment 1 in the similar approach described, from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-2, the 3-diphenylacrylate prepares free alkali; MS (ES +) 333 (MH +).
Embodiment 28
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-p-methoxy-phenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(4-methoxyl group) phenylacrylic acid; MS (ES +) 287 (MH +).
Embodiment 29
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-methyl-3-Phenyl Acrylamide)
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-2-methyl-3-phenylacrylic acid; MS (ES +) 271 (MH +).
Embodiment 30
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-methyl-3-Phenyl Acrylamide)
By with embodiment 1 in the similar approach described, prepare free alkali from (S)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-Alpha-Methyl-3-phenylacrylic acid; MS (ES +) 271 (MH +).
Embodiment 31
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-aminomethyl phenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-aminomethyl phenyl) vinylformic acid; MS (ES +) 271 (MH +).
Embodiment 32
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-aminomethyl phenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (S)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-aminomethyl phenyl) vinylformic acid; MS (ES +) 271 (MH +).
Embodiment 33
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-p-methoxy-phenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from racemize 1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-p-methoxy-phenyl) vinylformic acid; MS (ES +) 287 (MH +).
Embodiment 34
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-p-methoxy-phenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-p-methoxy-phenyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 287 (MH +).
Embodiment 35
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(4-p-methoxy-phenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from racemize 1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(4-p-methoxy-phenyl) vinylformic acid; MS (ES +) 287 (MH +).
Embodiment 36
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-fluorophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from racemize 1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-fluorophenyl) vinylformic acid; MS (ES +) 275 (MH +).
Embodiment 37
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-fluorophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-fluorophenyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 275 (MH +).
Embodiment 38
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-fluorophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(4-fluorophenyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 275 (MH +).
Embodiment 39
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-chloro-phenyl-) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-chloro-phenyl-) vinylformic acid; MS (ES +) 291 and 293 (MH +).
Embodiment 40
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-chloro-phenyl-) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (S)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-chloro-phenyl-) vinylformic acid; MS (ES +) 291 and 293 (MH +).
Embodiment 41
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-chloro-phenyl-) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-chloro-phenyl-) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 291,293 (MH +).
Embodiment 42
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-chloro-phenyl-) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(4-chloro-phenyl-) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 291,293 (MH +).
Embodiment 43
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3, the 4-dichlorophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3, the 4-dichlorophenyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 325,327,329 (MH +).
Embodiment 44
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-bromophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-bromophenyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 335,337 (MH +).
Embodiment 45
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-bromophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(4-bromophenyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 335,337 (MH +).
Embodiment 46
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-iodophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from racemize 1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-iodophenyl) vinylformic acid; MS (ES +) 357 (MH +).
Embodiment 47
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-iodophenyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from racemize 1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(4-iodophenyl) vinylformic acid; MS (ES +) 357 (MH +).
Embodiment 48
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-trifluoromethyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from racemize 1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-trifluoromethyl) vinylformic acid; MS (ES +) 325 (MH +).
Embodiment 49
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-trifluoromethyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-trifluoromethyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 271 (MH +).
Embodiment 50
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-furyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 247 (MH +).
Embodiment 51
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-furyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 247 (MH +).
Embodiment 52
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-pyridyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-pyridyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 258 (MH +).
Embodiment 53
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-pyridyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-pyridyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 258 (MH +).
Embodiment 54
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-pyridyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(3-pyridyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent.Product is dissolved in the methyl alcohol, adds excessive hydrogen chloride (1M is in ether).Evaporating solvent then, recrystallization from methyl alcohol/t-butyl methyl ether obtains the dihydrochloride into the title compound of colorless solid; MS (ES +) 258 (MH +).
Embodiment 55
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-thienyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 263 (MH +).
Embodiment 56
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide]
By with embodiment 1 in the similar approach described, from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and the preparation of E-3-(3-thienyl) vinylformic acid; Through Waters Bondapak  C 18Reversed-phase HPLC purifying compounds on the post uses acetonitrile and 0.1% trifluoroacetic acid aqueous solution as gradient eluent.From comprising the flow point evaporating solvent of product, then product is dissolved in the aqueous hydrochloric acid, evaporating solns obtains the hydrochloride into the title compound of colorless solid once more; MS (ES +) 282 (MH +).
Embodiment 57
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-nitro-2-furyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(5-nitro-2-furyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 293 (MH +).
Embodiment 58
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(5-methoxyl group-3-pyridyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 288 (MH +).
Embodiment 59
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(5-hydroxyl-3-pyridyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 274 (MH +).
Embodiment 60
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (R)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(4-imidazolyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent; MS (ES +) 247 (MH +).
Embodiment 61
N-(interior-the 8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide)
At room temperature, with 3 alpha-amino group tropane dihydrochlorides (3.6g), E-phenylacrylic acid (2.5g), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (3.2g) and triethylamine (12mL) are at N, and the mixed solution in the dinethylformamide (30mL) stirs and spends the night.Evaporating solns distributes resistates between aqueous sodium hydroxide solution and chloroform.Evaporating solns is through WatersBondapak  C 18Reversed-phase HPLC purifying resistates on the post uses acetonitrile and 0.1% trifluoroacetic acid aqueous solution as gradient eluent.Comprise the flow point of product through evaporation, in methyl alcohol, dissolve resistates, add excessive hydrogen chloride solution (1M is in ether) and evaporation, the preparation hydrochloride.After the vacuum-drying, obtain dihydrochloride (236mg) into the title compound of colorless solid; MS (ES +) 307 (MH +).
Embodiment 62
N-(outer-8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide)
At room temperature, with 3 beta-amino tropane dihydrochlorides (1.83g), E-3-phenylacrylic acid (1.57mg), I-hydroxybenzotriazole hydrate (1.16g), Tetrafluoroboric acid O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea (2.76g) and N, N-diisopropylethylamine (6.0mL) is at N, and the mixed solution in the dinethylformamide (15mL) stirs and spends the night.Evaporating solns distributes resistates between aqueous sodium hydroxide solution and chloroform.Evaporating solns is through Waters Bondapak  C 18Reversed-phase HPLC purifying resistates on the post uses acetonitrile and 0.1% trifluoroacetic acid aqueous solution as gradient eluent.Comprise the flow point of product through evaporation, in methyl alcohol, dissolve resistates, add excessive hydrogen chloride solution (1M is in ether) and evaporation, the preparation hydrochloride.After the vacuum-drying, obtain dihydrochloride (243mg) into the title compound of colorless solid; MS (ES +) 307 (MH +).
Embodiment 63
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide]
By with embodiment 1 in the similar approach described, prepare free alkali from (S)-1-azabicyclo [2.2.2] oct-3-yl amine dihydrochloride and E-3-(2-furyl) vinylformic acid; Through the silica gel chromatography purifying compounds, use to contain ammonia methyl alcohol/chloroform mixture as eluent, recrystallization from ethyl acetate/hexane; MS (ES +) 247 (MH +).

Claims (24)

1. the compound of general formula I or its enantiomorph or its pharmacy acceptable salt are used to prepare the purposes for the treatment of or preventing the medicine of psychosis or intellectual damage disease,
Figure C008184210002C1
Wherein:
A represents:
D represents oxygen or sulphur;
R 1Expression hydrogen or methyl;
R 2Expression hydrogen or C 1-C 4Alkyl;
R 3Expression:
Figure C008184210002C3
Or
R 4, R 5And R 6Independent is hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl ,-CO 2R 7,-CN ,-CF 3Or Ar, condition is R 4And R 5In at least one the expression Ar;
Ar represents to comprise 5-or the 6-unit's aromatics or the heteroaromatic rings of 0-3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, 8-, the 9-or 10-unit's fused aromatic or the heteroaromatic rings system that perhaps comprise 0-4 nitrogen-atoms, a 0-1 Sauerstoffatom and 0-1 sulphur atom, it can be selected from by one or more, and following substituting group is optional to be replaced, and comprising: hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, aryl, heteroaryl ,-CO 2R 7,-CN ,-NO 2,-NR 8R 9,-CF 3,-OR 10
R 8, R 9And R 10Independent is hydrogen, C 1-C 4Alkyl, aryl, heteroaryl ,-C (O) R 11,-C (O) NHR 12,-C (O) R 13,-SO 2R 14, or R 8And R 9Can be (CH together 2) jQ (CH 2) k, wherein Q is O, S, NR 15Or key;
J is 2-4;
K is 0-2;
R 7, R 10, R 11, R 12, R 13, R 14And R 15Independent is C 1-C 4Alkyl, aryl or heteroaryl,
Condition is that the compound of wherein said formula I is not ethyl-3-[2-(3-rubane carbamyl) vinyl] 4,6-dichloro-indole-2-carboxylicesters or 3-[2-(3-rubane carbamyl) vinyl] 4,6-dichloro-indole-2-carboxylic acid.
2. the purposes of claim 1, wherein:
A represents:
Figure C008184210003C1
3. the purposes of claim 1 or claim 2, wherein D represents oxygen.
4. each purposes, wherein R among the claim 1-3 2Expression hydrogen.
5. each purposes, wherein R among the claim 1-4 3Expression
Figure C008184210003C2
6. each purposes among the claim 1-4, wherein:
R 3Expression
R 4Expression Ar;
R 5Expression hydrogen or C 1-C 4Alkyl; With
R 6The expression hydrogen or halogen.
7. the purposes of claim 1, wherein:
A represents
Figure C008184210004C2
D represents oxygen;
R 2Expression hydrogen; With
R 3Expression
8. the purposes of claim 1, its Chinese style I compound is a kind of compound, wherein:
A represents
D represents oxygen;
R 2Expression hydrogen;
R 3Expression
R 4Expression Ar;
R 5Expression hydrogen or C 1-C 4Alkyl; With
R 6The expression hydrogen or halogen.
9. each purposes among the claim 1-8, wherein Ar represents to comprise 5-or the 6-unit's aromatics or the heteroaromatic rings of 0-3 nitrogen-atoms, 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom, 8-, the 9-or 10-unit's fused aromatic or the heteroaromatic rings system that perhaps comprise 0-4 nitrogen-atoms, a 0-1 Sauerstoffatom and 0-1 sulphur atom, it can be selected from by one or more, and following substituting group is optional to be replaced, and comprising: hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, aryl, heteroaryl ,-CO 2R 7,-CN ,-NO 2,-NR 8R 9,-CF 3With-OR 10
10. the purposes of claim 1, wherein said compound is:
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) (3-phenyl propine acid amides);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [Z-3-(2-p-methoxy-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl)-N-methyl-(E-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-2-benzyl ring propane-1-methane amide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-2-fluoro-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-formamido-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-nitrophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-(4-aminophenyl) acrylamide;
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-formamido-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-methyl-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N-methylamino phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N, N-dimethylaminophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-methyl-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2,3-phenylbenzene propylene acid amides);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-p-methoxy-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-methyl-3-Phenyl Acrylamide);
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminomethyl phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-p-methoxy-phenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-fluorophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-fluorophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-chloro-phenyl-) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-chloro-phenyl-) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-chloro-phenyl-) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3, the 4-dichlorophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-bromophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-bromophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-iodophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-iodophenyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-trifluoromethyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-trifluoromethyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-nitro-2-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide];
N-(interior-the 8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide);
N-(outer-8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide);
Or its enantiomorph or its pharmacy acceptable salt.
11. the purposes of claim 1, wherein said compound is:
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide);
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide);
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (3-phenyl propine acid amides);
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (3-phenyl propine acid amides);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-nitrophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [Z-3-(2-p-methoxy-phenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl)-N-methyl-(E-3-Phenyl Acrylamide);
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-2-benzyl ring propane-1-methane amide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-2-benzyl ring propane-1-methane amide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-2-fluoro-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-formamido-phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-nitrophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-(4-aminophenyl) acrylamide;
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-formamido-phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-methyl-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N-methylamino phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-N, N-dimethylaminophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (Z-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-3-methyl-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2,3-phenylbenzene propylene acid amides);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-p-methoxy-phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-methyl-3-Phenyl Acrylamide);
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) (E-2-methyl-3-Phenyl Acrylamide);
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminomethyl phenyl) acrylamide];
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-aminomethyl phenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-p-methoxy-phenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-p-methoxy-phenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-p-methoxy-phenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-fluorophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-fluorophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-fluorophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-chloro-phenyl-) acrylamide];
(S)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-(2-chloro-phenyl-) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-chloro-phenyl-) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-chloro-phenyl-) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3, the 4-dichlorophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-bromophenyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-bromophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-iodophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-iodophenyl) acrylamide];
(RS)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-trifluoromethyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-trifluoromethyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-nitro-2-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide];
N-(interior-the 8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide);
N-(outer-8-azepine-8-methyl bicycle [3.2.1] oct-3-yl) (E-3-Phenyl Acrylamide);
Or its enantiomorph or its pharmacy acceptable salt.
12. the compound of a general formula I or its enantiomorph or its pharmacy acceptable salt,
Figure C008184210010C1
Wherein:
A represents:
Figure C008184210010C2
Or
；
D represents oxygen or sulphur;
R 1Expression hydrogen or methyl;
R 2Expression hydrogen or C 1-C 4Alkyl;
R 3Expression:
Or
R 4, R 5And R 6Independent is hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl ,-CO 2R 7,-CN ,-CF 3Or Ar, condition is R 4And R 5In at least one the expression Ar;
Ar represents thienyl, furyl, pyridyl or imidazolyl, and it can be selected from by one or more, and following substituting group is optional to be replaced, and comprising: hydrogen, halogen, C 1-C 4Alkyl, C 2-C 4Alkenyl, C 2-C 4Alkynyl, aryl, heteroaryl ,-CO 2R 7,-CN ,-NO 2,-NR 8R 9,-CF 3,-OR 10
R 8, R 9And R 10Independent is hydrogen, C 1-C 4Alkyl, aryl, heteroaryl ,-C (O) R 11,-C (O) NHR 12,-C (O) R 13Or-SO 2R 14, perhaps R 8And R 9Can be (CH together 2) jQ (CH 2) k, wherein Q is O, S, NR 15Or key;
J is 2-4;
K is 0-2;
R 7, R 10, R 11, R 12, R 13, R 14And R 15Independent is C 1-C 4Alkyl, aryl or heteroaryl, condition are that Ar does not represent to be selected from 2-, 3-, the 4-pyridyl that following substituting group replaces by one or more, comprising: C 1-C 4Alkyl, C 1-C 4Alkoxyl group, halogen, phenoxy group, hydroxyl, OCOR 11, NH 2, NHCOR 11And nitro,
When A represents
During II;
R 3Expression:
Figure C008184210012C1
D represents oxygen;
R 2And R 5All represent hydrogen; With
R 6Expression hydrogen, C 1-C 4In alkyl, phenyl or the cyano group any,
Condition is that the compound of wherein said formula I is not ethyl-3-[2-(3-rubane carbamyl) vinyl] 4,6-dichloro-indole-2-carboxylicesters or 3-[2-(3-rubane carbamyl) vinyl] 4,6-dichloro-indole-2-carboxylic acid.
13. the compound of a claim 12, wherein A represents:
Or its enantiomorph or its pharmacy acceptable salt.
14. the compound of a claim 13 or its enantiomorph or its pharmacy acceptable salt, wherein R 4In expression 2-furyl, 3-furyl, 2-thienyl, the 3-thienyl any one.
15. the compound of a claim 12, described compound is:
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-nitro-2-furyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide];
N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide];
Or its enantiomorph or its pharmacy acceptable salt.
16. the compound of a claim 12, described compound is:
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-furyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(2-thienyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(3-thienyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-methoxyl group-3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(5-hydroxyl-3-pyridyl) acrylamide];
(R)-N-(1-azabicyclo [2.2.2] oct-3-yl) [E-3-(4-imidazolyl) acrylamide];
Or its enantiomorph or its pharmacy acceptable salt.
17. each defined compound is used for the treatment of or prevents wherein to activate purposes in the medicine of disease that alpha 7 nicotinic acetylcholine receptors is useful people or symptom in preparation among the claim 12-16.
18. each defined compound is used for the treatment of or prevents purposes in the medicine of following disease in preparation among the claim 12-16, described disease comprises: presenile dementia, the study defective, cognitive defect, absent minded, the loss of memory, scatterbrained hyperactivity disorder, anxiety disorder, schizophrenia, manic or manic depressive illness, thunder dimension corpusculum dementia, Parkinson's disease, Huntington Chorea, Tourette's syndrome, the neurodegenerative disease of cholinergic synapse forfeiture wherein, jet lag, stop smoking, comprise and be exposed to the nicotine habituation that the product that contains nicotine causes, pain or ulcerative colitis.
19. the purposes of claim 18, wherein said symptom or disease are presenile dementia, study defective, cognitive defect, absent minded, the loss of memory, thunder dimension corpusculum dementia or scatterbrained hyperactivity disorder.
20. the purposes of claim 18, wherein said disease are anxiety disorder, schizophrenia or manic or manic depressive illness.
21. the purposes of claim 18, wherein said disease are Parkinson's disease, Huntington Chorea, Tourette's syndrome or the neurodegenerative disease of cholinergic synapse forfeiture wherein.
22. the purposes of claim 18, wherein said symptom or disease be jet lag, comprise and be exposed to nicotine habituation, pain or the ulcerative colitis that the product that contains nicotine causes.
23. the purposes of claim 18, wherein said symptom or disease are presenile dementia.
24. a medicinal compositions, it comprise with inertia, pharmaceutically acceptable diluent or carrier blended claim 12-16 in each defined compound.
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